The present invention relates to phenylpyridazine compounds having excellent inhibitory activity against interleukin-1xcex2 production and methods for the prevention and treatment of immune system diseases, inflammatory diseases, ischemic diseases and the like using the compounds, and medicines containing them as active ingredients.
In many diseases, such as rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichoremia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease, Alzheimer""s disease, and leukemia, stimulation of the production of an inflammatory cytokine known as interleukin-1xcex2 is observed. Interleukin-1xcex2 serves to induce synthesis of an enzyme which is considered to take part in inflammation, such as collagenase and PLA2, and, when intra-articularly injected into animals, causes multiarticular destruction highly resembling rheumatoid arthritis. In the normal living body, on the other hand, interleukin-1xcex2 is controlled in activity by interleukin-1 receptors, soluble interleukin-1 receptor and interleukin-1 receptor antagonists.
From research conducted using recombinants of these bioactivity-inhibiting substances, anti-interleukin-1xcex2 antibodies, anti-receptor antibodies and knockout mice on various disease models, interleukin-1xcex2 has been found to play a pivotal role in the body, leading to an increasing potential of substances having interleukin-1xcex2 inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids used for the treatment of rheumatism have been reported to inhibit the production of interleukin-1xcex2. Even among medicines currently under development, KE298, a benzoylpropionic acid derivative [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to have inhibitory activity against interleukin-1xcex2 production, although it is an immunoregulator. Inhibitory activity against interleukin-1xcex2 production is also observed in a group of compounds called xe2x80x9cCOX-2 selective inhibitorsxe2x80x9d, including for example, nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap (oxyindole derivative) as a dual inhibitor (COX-1/5-LO).
For all of these compounds, however, interleukin-1xcex2 production inhibitory activity is not their primary action so that their inhibitory activity against interleukin-1xcex2 production is lower than their primary action.
In recent years, increasingly active research has been under way with a focus placed on inhibitory activity against interleukin-1xcex2 production. Production inhibitors can be classified into a group of compounds which inhibit the transmission process of an inflammatory signal to a cell nucleus and the transcription and translation process, and another group of compounds which inhibit an enzyme ICE that functions in the processing of a precursor of interleukin-1xcex2. Known examples of compounds presumed to have the former action include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 97/05878), while known examples of compounds presumed to have the latter action include VE-13,045 which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
However, none of these compounds exhibit sufficient inhibitory activity against interleukin-1xcex2 production.
On the other hand, it is known that a variety of 5,6-diphenylpyridazine derivatives have analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53-60, 1979). However, absolutely nothing has been known with respect to inhibitory activity of these 5,6-diphenylpyridazine derivatives against interleukin-1xcex2 production.
As pyridazine derivatives having inhibitory activity against interleukin-1xcex2 production, some pyridazine derivatives have been published recently in JP 7-69894, WO 9841511, WO 9910331, WO 9910332, WO 9925697 and WO 9944995. They are, however, different in chemical structure from the compounds according to the present invention.
There is thus a need for compounds capable of inhibiting interleukin-1xcex2 production.
Accordingly, one object of the present invention is to provide a compound having excellent inhibitory activity against interleukin-1xcex2 production.
A further object of the present invention is to provide a method for the treatment of diseases and conditions caused by stimulation of interleukin-1xcex2 production.
A further object of the present invention is to provide a pharmaceutical composition useful in treatment of diseases and conditions caused by stimulation of interleukin-1xcex2 production.
These and other objects of the present invention have been satisfied by the discovery of phenylpyridazine compounds of formula (I): 
wherein
R1, R2, R3, R4 and n have the meanings disclosed herein, which has excellent inhibitory activity against interleukin-1xcex2 production, and their use in pharmaceutical compositions and methods for treating diseases caused by stimulation of interleukin-1xcex2 production.
The present invention relates to pyridazine compounds represented by formula (I) having excellent inhibitory activity against interleukin-1xcex2 production and useful as medicines for the prevention and treatment of immune system diseases, inflammatory diseases and ischemic diseases.
The phenylpyridazine compound of the present invention is represented by the following formula (I): 
wherein
R1 represents a substituted or unsubstituted phenyl group or a substituted or unsubstituted pyridyl group,
R2 represents a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group or a lower alkylsulfonyl group;
R3 represents a hydrogen atom or a lower alkoxy group,
or R2 and R3 may be fused together to form an alkylenedioxy group,
R4 represents hydrogen, halogen, cyano, carboxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkylthio, substituted or unsubstituted lower alkylsulfinyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted lower alkylsulfonyloxy, substituted or unsubstituted aryl, substituted or unsubstituted phenoxy, substituted or unsubstituted phenylthio, substituted or unsubstituted phenylsulfinyl, substituted or unsubstituted phenylsulfonyl, substituted or unsubstituted pyridyloxy, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinocarbonyl, substituted or unsubstituted piperidinocarbonyl, substituted or unsubstituted 1-piperazinylcarbonyl or substituted or unsubstituted amino, and
n is 0 or 1,
with the proviso that when R1 is 4-methoxyphenyl group, R2 is a methoxy group and R3 is a hydrogen atom, R4 can not be hydrogen or halogen, and also R1 can not be 4-(methylsulfonyl)phenyl or 4-(aminosulfonyl)phenyl;
or a salt thereof.
The present invention also provides a composition comprising the phenylpyridazine compound (I) or the salt thereof as an effective ingredient, in a suitable pharmaceutically acceptable carrier.
Moreover, the present invention also provides a method for treating a disease caused by stimulation of interleukin-1xcex2 production, which comprises administering to a subject in need thereof, an effective amount of the phenylpyridazine compound (I) or the salt thereof, either alone or as a composition in a pharmacologically acceptable carrier.
Within the context of the present invention, the term xe2x80x9clower alkylxe2x80x9d represents alkyl groups having from 1 to 6 carbons and being either linear, branched or cyclic.
Illustrative of the lower alkyl group and the lower alkyl moieties in the lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group and lower alkylsulfonyloxy group as used herein are linear, branched or cyclic lower alkyl groups having 1 to 6 carbon atoms, such as, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-methyl butyl, 2,2-dimethyl propyl, cyclopentyl, cyclohexyl, n-hexyl, 2-methyl pentyl, 3-methyl pentyl, 2,2-dimethyl butyl and 2,3-dimethylbutyl groups. Examples of the halogen atom can include fluorine, chlorine, bromine and iodine atoms.
Examples of one or more substituent groups on the substituted phenyl or pyridyl group represented by R1 in the formula (I) include halogen, hydroxyl, alkyl, lower alkoxy and phenylthio groups, with halogen, lower alkoxy or phenylthio groups being particularly preferred. As the halogens, fluorine or chlorine are preferred, and as lower alkoxy groups, methoxy is preferred. These substituent groups are preferably substituted to the 4-position of a phenyl group, although they may be present at any other position as desired. A preferred R1 group is a pyridyl group or a phenyl group substituted by one or more halogens, lower alkoxy or phenylthio groups. More preferred R1 groups are 4-methoxyphenyl, 4-pyridyl, phenyl, 4-fluorophenyl, 4-chlorophenyl or 4-(phenylthio)phenyl.
As the lower alkyl moiety in lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl groups represented by R2, methyl is especially preferred. Most preferred R2 groups are methoxy, methylthio or methylsulfonyl.
As the lower alkoxy group represented by R3, methoxy is particularly preferred.
Further, when R2 and R3 combine to form an alkylenedioxy group, ethylenedioxy is preferred.
Examples of one or more substituent groups on the substituted lower alkyl groups represented by R4include halogen, hydroxy, cyano, nitro, amino, carboxy, and substituted or unsubstituted aminocarbonyl groups. Illustrative of one or more substituent groups on the aminocarbonyl group are hydroxyl and lower alkyl groups. Examples of one or more substituent groups on the substituted lower alkenyl group represented by R4 include halogen and aryl groups. Examples of the lower alkenyl group include linear, branched or cyclic lower alkenyl groups having 1 to 6 carbon atoms, with an allyl group being particularly preferred. Examples of one or more substituent groups on substituted lower alkylthio, substituted lower alkylsulfinyl, substituted lower alkylsulfonyl or substituted lower alkylsulfonyloxy represented by R4 include aryl groups. Illustrative of one or more substituent groups on the substituted aryl group represented by R4 are halogen, lower alkyl, lower alkoxy, cyano, nitro, and amino groups, with halogen and lower alkyl groups being particularly preferred. Examples of the aryl group include phenyl and pyridyl, with phenyl being particularly preferred. Examples of one or more substituent groups on the substituted phenoxy group represented by R4 include halogen, cyano, nitro, amino, lower alkyl and lower alkoxy groups, among which halogen, cyano, nitro and lower alkoxy groups are particularly preferred. Illustrative of one or more substituent groups on substituted phenylthio, substituted phenylsulfinyl or substituted phenylsulfonyl groups represented by R4 are halogen, lower alkyl, lower alkoxy, cyano, nitro and amino groups, with halogen being particularly preferred. Illustrative of one or more substituent groups on the substituted pyridyloxy group represented by R4 are halogen, lower alkyl, lower alkoxy, cyano, nitro, and amino groups. Illustrative of one or more substituent groups on substituted morpholino, substituted morpholinocarbonyl or substituted piperidinocarbonyl groups represented by R4 are halogen, lower alkyl, lower alkoxy, cyano and nitro groups. Illustrative of one or more substituent groups on the substituted 1-piperazinylcarbonyl group represented by R4 are halogen, lower alkyl, lower alkoxy, cyano, nitro and amino groups, with lower alkyl groups being particularly preferred. Illustrative of one or more substituent groups on the substituted amino group represented by R4 are lower alkyl, substituted or unsubstituted phenyl, benzyl, or acyl groups, among which lower alkyl, substituted or unsubstituted phenyl and benzyl groups are preferred. Examples of the substituent groups on the phenyl group include halogen, cyano, nitro, amino and lower alkoxy groups, with halogen and alkoxy groups being preferred.
Preferred group as R4 is hydrogen; halogen; cyano; carboxyl; lower alkyl, which may be substituted by one or more groups selected from hydroxyl, carboxyl or substituted or unsubstituted aminocarbonyl groups; lower alkenyl; lower alkylthio; lower alkylsulfonyl; lower alkylsulfonyloxy; phenyl; phenoxy, which may be substituted by one or more groups selected from halogens, cyano, nitro or lower alkoxy groups; phenylthio, which may be substituted by one or more halogen atoms; pyridyloxy; morpholino; morpholinocarbonyl; 1-piperazinylcarbonyl, which may be substituted by one or more lower alkyl groups; or amino, which may be substituted by one or more members selected from lower alkyl, substituted or unsubstituted phenyl, or benzyl groups.
In the phenylpyridazine derivative of formula (I) according to the present invention, R1 represents a substituted or unsubstituted phenyl group or a pyridyl group, R2 represents lower alkoxy, lower alkylthio or lower alkylsulfonyl, R3 represents hydrogen or lower alkoxy, or R2 and R3 may be fused together to form an alkylenedioxy group. R4 represents hydrogen, halogen, cyano, carboxy, substituted or unsubstituted lower alkyl, lower alkenyl, lower alkylthio, lower alkylsulfonyl, a lower alkyl sulfonyloxy, substituted or unsubstituted aryl, substituted or unsubstituted phenoxy, a substituted or unsubstituted phenylthio, pyridyloxy, morpholino, morpholinocarbonyl, substituted or unsubstituted 1-piperazinylcarbonyl or substituted or unsubstituted amino, and n represens 0 or 1, with a proviso that a phenylpyridazine derivative of the formula (I) in which R4 is a hydrogen or halogen atom, R1 is 4-methoxyphenyl, R2 is methoxy and R3 is hydrogen is excluded; or that a phenylpyridazine derivative of the formula (I) in which R1 is 4-(methylsulfonyl)phenyl or 4-(aminosulfonyl)phenyl is excluded. More preferred specific examples of the phenylpyridazine compound (I) according to the present invention include 3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,5-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,6-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetrafluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenylthio)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2-cyanophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3-cyanophenoxy)pyridazine, 6-(2,4-difluorophenoxy)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine, 6-(2,3-difluorophenoxy)-3-(4-methoxyphenyl)-4-phenylpyridazine, 6-(2,4-difluorophenoxy)-3-(4-methoxyphenyl)-4-phenylpyridazine, 3-(4-methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpyridazine, 3-(4-methylthiophenyl)-6-phenylthio-4-(4-phenylthiophenyl)pyridazine, 4-(4-chlorophenyl)-6-(2,4-difluorophenoxy)-3-[4-(methylthio)phenyl]pyridazine, 3,4-bis(4-methoxyphenyl)-6-cyanopyridazine, and 6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazine.
No particular limitation is imposed on the process for the preparation of the phenylpyridazine compound (I) or a salt thereof of the present invention, and various processes, which have conventionally been used for the synthesis of pyridazine derivatives, and their modifications can be used. For example, the phenylpyridazine compound (I) or a salt thereof of the present invention can be prepared in accordance with the reaction schemes of any one of the following preparation processes 1-5. 
wherein R1, R2 and R3 have the same meanings as defined above, R5 represents substituted or unsubstituted morpholino, substituted or unsubstituted piperidino, substituted or unsubstituted 1-piperazinyl, or the like, and R6 and R7 each independently represent hydrogen, hydroxy, lower alkyl, or the like.
In preparation process 1, starting material compounds (II) and (III) can be prepared by known processes (WO 9925697).
The following description preparation method provides suitable solvents, reactants, catalysts and conditions for each reaction. However, it is to be understood that these are merely illustrative in nature and are not intended to be limiting of the present invention.
(1) Preparation of Compound (I1) in which R4 Is Halogen
The compound (I1) can be prepared by reacting a halogenating agent with compound (II) in a solvent.
Suitable solvents usable in this reaction include benzene, toluene and N,N-dimethylformamide (DMF). Suitable halogenating agents are phosphorus oxychloride and thionyl chloride. It is preferred to conduct the reaction at 20 to 150xc2x0 C. for 0.5 to 10 hours, more preferably at 50 to 130xc2x0 C. for 1 to 5 hours.
(2) Preparation of Compound (I2) in which R4 Is Substituted or Unsubstituted Phenoxy, Compounds (I3) in which R4 Is Substituted or Unsubstituted Phenylthio, Compound (I4) in which R4 Is Substituted or Unsubstituted Pyridyloxy, Compound (I5) in which R4Is Substituted or Unsubstituted Morpholino, or Compound (I6) in which R4 Is Substituted or Unsubstituted Amino
The compounds (I2-I6) can each be prepared by reacting the corresponding compound (I1) with R4xe2x80x2 H, in which R4xe2x80x2 represents substituted or unsubstituted phenoxy, substituted or unsubstituted phenylthio, substituted or unsubstituted pyridyloxy, substituted or unsubstituted morpholino or substituted or unsubstituted amino, in the presence of a base in solvent.
Suitable bases include inorganic bases such as potassium carbonate, sodium carbonate and sodium hydride; and organic bases such as metal alkoxides. Examples of suitable solvents include DMF, dimethyl sulfoxide, acetone and methyl ethyl ketone. It is preferred to conduct the reaction at 20 to 150xc2x0 C. for 1 to 20 hours, more preferably at 50 to 130xc2x0 C. for 2 to 10 hours.
(3) Preparation of Compound (I7) in which R4 Is Substituted or Unsubstituted Aryl
Compound (I7) can be prepared by dissolving the corresponding compound (I1) in a solvent, successively adding a palladium catalyst and an arylmagnesium bromide, and then reacting them.
Suitable solvents for this reaction include diethyl ether, tetrahydrofuran (THF), dimethoxyethane, benzene and toluene. Examples of the palladium catalyst include palladium chloride and tetrakis(triphenylphosphine)palladium. It is preferred to conduct the reaction at 20 to 100xc2x0 C. for 0.5 to 2 hours, more preferably at 40 to 80xc2x0 C. for 1 to 1.5 hours.
(4) Preparation of Compound (I8) in which R4 Is Alkylthio
Compound (I8) can be prepared by reacting an alkyl halide with the corresponding compound (III) in the presence of sodium hydride in a solvent.
Suitable solvent for this reaction include DMF, dimethyl sulfoxide, acetone, THF, dioxane and methyl ethyl ketone. It is preferred to conduct the reaction under stirring at 0 to 50xc2x0 C. for 0.5 to 2 hours, more preferably at 5 to 20xc2x0 C. for 1 hour.
(5) Preparation of Compound (I9) in which R4 Is Alkylsulfonyl
Compound (I9) can be prepared by oxidizing the corresponding compound (I8) in a solvent.
Suitable oxidizing agents include osmium tetraoxide-sodium periodate or methachloroperbenzoic acid. As the solvent, chloroform, acetone, butanol or the like or a mixed solvent thereof can be used. It is preferred to conduct the reaction under stirring at xe2x88x9240 to 50xc2x0 C. for 1 to 40 hours, more preferably at xe2x88x9210 to 20xc2x0 C. for 10 to 30 hours.
(6) Preparation of Compound (I10) in which R4 is Alkylsulfonyloxy
Compound (I10) can be prepared by reacting the corresponding compound (II) with an alkylsulfonyl chloride in a solvent.
Suitable solvents include pyridine, picoline and lutidine. It is preferred to conduct the reaction at 10 to 40xc2x0 C. for 1 to 10 days, more preferably at 20 to 30xc2x0 C. for 3 to 5 days.
(7) Preparation of Compound (I11) in which R4 Is Hydrogen
Compound (I11) can be prepared by subjecting the corresponding compound (I1) to catalytic reduction in the presence of a catalyst in a solvent.
Suitable solvents include methanol, ethanol, THF, ethyl acetate and acetic acid. As the catalyst, 10% palladium on charcoal can be used. It is preferred to conduct the reaction under a hydrogen gas stream at room temperature under atmospheric pressure for 1 to 10 hours, more preferably for 4 to 5 hours.
(8) Preparation of Compound (I12) in which R4 Is Hydrogen, Namely, of Pyridazine 1-oxide Compound
Compound (I12) can be prepared by reacting the corresponding compound (I11) with hydrogen peroxide solution in a solvent.
A suitable solvent is acetic acid. It is preferred to conduct the reaction at 20 to 80xc2x0 C. for 2 to 10 hours, more preferably at 40 to 60xc2x0 C. for 4 to 6 hours.
(9) Preparation of Compound (I13) in which R4 Is Cyano
Compound (I13) can be prepared by reacting the corresponding compound (I12) with an acylating agent and an alkali cyanide in a solvent.
Suitable alkali cyanides include sodium cyanide and potassium cyanide. As the acylating agent, acetic anhydride, acetyl chloride, benzoyl chloride or the like can be used. It is preferred to conduct the reaction at 10 to 40xc2x0 C. for 10 to 40 hours, more preferably at 20 to 30xc2x0 C. for 20 to 30 hours.
(10) Preparation of Compound (I14) in which R4 Is Carboxyl
Compound (I14) can be prepared by hydrolyzing the corresponding compound (I13) in the presence of an inorganic acid or an alkali in a solvent.
Suitable solvents include water, ethanol, methanol, and mixed solvents thereof. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid or the like can be used. As the alkali, sodium hydroxide, potassium hydroxide or the like can be used. It is preferred to conduct the reaction under stirring at 60 to 140xc2x0 C. for 0.5 to 2 hours, more preferably at 80 to 120xc2x0 C.
(11) Preparation of Compound (I15) in which R4 Is xe2x80x94COR5 
Compound (I15) can be prepared by reacting a compound, which is represented by the formula R5H in which R5 has the same meaning as defined above, with the corresponding compound (I14) in the presence of a condensing agent.
Suitable condensing agents include a 50% solution of cyclic 1-propanephosphoric anhydride (n=3) in ethyl acetate. As the solvent, THF, DMF or a mixed solvent thereof can be used. It is preferred to conduct the reaction under stirring at 10 to 40xc2x0 C. for 1 to 7 hours, more preferably at 20 to 30xc2x0 C. for 3 to 5 hours.
(12) Preparation of Compound (I16) in which R4 Is Alkenyl
Compound (I16) can be prepared by reacting an alkenylmagnesium bromide with the corresponding compound (I1) in the presence of a palladium catalyst in a solvent under an inert gas atmosphere.
Suitable solvents include THF, benzene and toluene. As the palladium catalyst, palladium chloride, tetrakis(triphenylphosphine)palladium or the like are preferred. It is preferred to conduct the reaction at xe2x88x9220 to 40xc2x0 C. for 0.5 to 4 hours, more preferably at xe2x88x9210 to 10xc2x0 C. for 0.5 to 1.5 hours, followed by further reaction at 20 to 30xc2x0 C. for 1 to 3 hours.
(13) Preparation of Compound (I17) in which R4 Is Hydroxyalkyl
Compounds (I17) can be prepared by subjecting the alkenyl group of the corresponding compound (I16) to a hydroboration reaction.
The hydroboration reaction can be conducted, for example, by adding a solution of 9-borabicyclo[3.3.1]nonane (9-BBN) or a salt thereof to a solvent, in which the compound (I16) is contained, under an atmosphere of an inert gas, such as argon or nitrogen, stirring the resulting mixture at 10 to 40xc2x0 C. for 5 to 30 hours, preferably at 20 to 30xc2x0 C. for 10 to 20 hours, successively adding water, an aqueous solution of an alkali and hydrogen peroxide solution to the reaction mixture while cooling it with ice water, and then stirring the thus-obtained mixture at 10 to 40xc2x0 C. for 1 to 4 hours, preferably at 20 to 30xc2x0 C. for 1.5 to 3 hours.
(14) Preparation of Compound (I18) in which R4 Is Carboxyalkyl
Compound (I18) can be prepared by subjecting the compound (I17) to an oxidation reaction with an oxidizing agent in a solvent.
Suitable solvents include acetone and acetic acid. As the oxidizing agent, Jones reagent is preferred. It is preferred to conduct the reaction at 10 to 40xc2x0 C. for 4 to 12 hours, more preferably at 20 to 30xc2x0 C. for 6 to 10 hours.
(15) Preparation of Compound (I19) in which R4 Is Alkyl Substituted by Substituted or Unsubstituted Aminocarbonyl
Compound (I19) can be prepared by reacting the corresponding compound (I18) and a compound represented by R6R7NH, in which R6 and R7 have the same meanings as defined above, in the same manner as in the preparation of the compound (I15). 
Preparation of Compound (I20) in which R2 Is Lower Alkylsulfonyl
Compound (I20) can be prepared by oxidizing the corresponding compound (IV) in a solvent.
As this reaction, a reaction similar to that employed in the preparation of compound (I9) can be used. Alternatively, hydrogen peroxide or the like can be used as the oxidizing agent, and acetic acid or the like can be used as the solvent. In this case, it is preferred to conduct the reaction at 40 to 100xc2x0 C. for 0.5 to 6 hours, more preferably at 60 to 80xc2x0 C. for 2 to 4 hours. 
Preparation of Compound (I21) in which R1 Is Phenylthiophenyl and R4 Is Phenylthio
Compound (I21) can be prepared by reacting a corresponding compound (I1), in which R1 is a halophenyl group, with thiophenol in the presence of a base in a solvent.
Suitable bases include inorganic bases such as potassium carbonate, sodium carbonate and sodium hydride; and organic bases such as metal alkoxides. As the solvent, DMF, dimethyl sulfoxide, acetone, methyl ethyl ketone or the like can be used. It is preferred to conduct the reaction at 50 to 300xc2x0 C. for 5 to 40 hours, more preferably at 100 to 200xc2x0 C. for 10 to 30 hours. 
In the preparation process 4, compound (VII) can be prepared by reacting acetone with the compound (V) in the presence of a base in a solvent.
Suitable solvents include acetone, ethanol, methanol, and mixed solvents thereof Examples of the base include piperidine, morpholine and diisopropylamine. It is preferred to conduct the reaction with stirring at 10 to 40xc2x0 C. for 10 minutes to 1 hour, more preferably for 20 to 40 minutes. Alternatively, as compound (VII), the commercial product available from Lancaster can also be used.
(1) Preparation of Compound (I22) in which R4 Is Alkyl
Compound (I22) can be prepared by reacting compound (VI) and compound (VII) in the presence of an alkali cyanide in a solvent to obtain compound (VIII), reacting hydrazine hydrate with compound (VIII) in a solvent, and then conducting dehydrogenation.
Suitable solvents for the reaction between compound (VI) and compound (VII) include DMF and dimethylsulfoxide, and examples of the alkali cyanide include potassium cyanide and sodium cyanide.
Suitable solvents for the reaction with hydrazine hydrate include ethanol and isopropanol.
It is preferred to conduct the reaction under stirring at 50 to 100xc2x0 C. for 4 to 10 hours, more preferably at 70 to 90xc2x0 C. for 6 to 8 hours. The dehydrogenation reaction can be conducted by air oxidation in a solvent such as chloroform.
(2) Preparation of Compound (I23) in which R2 Is Alkylsulfonyl and R4 Is Alkyl
Compound (I23) can be prepared by reacting a corresponding compound (I22), in which R2 is alkylthio, in a similar manner as in the preparation of compound (I20). 
In preparation process 5, compound (IX) can be prepared by a known process (WO 9925697). Compound (X) can be obtained by adding lithium diisopropylamide (LDA) at xe2x88x9220xc2x0 C. to a solution of compound (IX) in THF, reacting them at room temperature for 20 minutes, adding allyl iodide and then reacting them at room temperature for 30 minutes. Compound (XI) can be prepared by oxidizing compound (X) with osmium tetraoxide, similar to the procedure discussed earlier.
(1) Preparation of Compound (I24) in which R1 Is Halophenyl and R4 Is Hydrogen
Compound (I24) can be prepared by reacting compound (XI) in a similar manner as in the preparation of compound (I22).
(2) Preparation of Compound, Pyridazine 1-oxide, (I25) in which R1 Is Halophenyl and R4 Is Hydrogen
Compound (I25) can be prepared by reacting compound (I24) in a similar manner as in the preparation of compound (I12).
(3) Preparation of Compound (I26) in which R1 Is Halophenyl and R4 Is Cyano
Compound (I26) can be prepared by reacting compound (I25) in a similar manner as in the preparation of compound (I13).
The intermediates and target compounds obtained in the above-described individual reactions can be separated and purified by purification methods commonly employed in synthetic organic chemistry, including, but not limited to, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographic methods. The intermediates may be provided for the next reactions without purifying them or can be purified as desired, using conventional purification methods. Further, they may also be obtained as solvates of solvents such as reaction solvents or recrystallization solvents, especially as hydrates.
Examples of the salt of the phenylpyridazine compound of the present invention, are the hydrochloride, nitrate, hydrobromide, acetate, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, methylammonium salt, dimethylammonium salt, and trimethylammonium.
The phenylpyridazine compounds (I) and their salts according to the present invention, have excellent inhibitory activity against interleukin-1xcex2 production, and are useful for the prevention and treatment of diseases caused by stimulation of interleukin-1xcex2 production. Many diseases are caused by this stimulation of interleukin-1xcex2 production, such as immune system diseases, inflammatory diseases, ischemic diseases, osteoporosis and ichoremia. The present compounds or salts are particularly useful as medicines such as preventives and therapeutics for rheumatism, immune deficiency syndrome, arthritis, inflammatory colitis, ischemic heart diseases, ischemic encephalopathy, ischemic nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson""s disease and Alzbeimer""s disease, and leukemia or as interleukin-1xcex2 production inhibitors.
Pharmaceutical compositions according to the present invention contain the phenylpyridazine compounds (I) or its salt as an active ingredient. Any administration route can be used for the composition, including but not limited to, oral administration by tablets, capsules, granules, powders or syrups and parenteral administration by intravenous injections, intramuscular injections, suppositories, inhalants, transdermal preparations, eye drops or nasal drops. Upon formulation of pharmaceutical compositions of these various unit dosage forms, the active ingredients can be used alone or in combination with conventional pharmaceutically acceptable excipients, binders, extenders, disintegrators, surfactants, lubricants, dispersants, buffers, preservatives, corrigents, perfumes, coating agents, vehicles, diluents and/or carriers as desired.
The dosage of each pharmaceutical composition according to the present invention varies depending on the body weight, age, sex and condition of the patient. In the case of an adult, however, it is generally preferred to orally or parenterally administer the compound represented by the formula (I) in an amount of from about 0.01 to 1,000 mg, preferably 0.1 to 100 mg per day at once or in several portions. If administered in several portions, the several portions can be equal to one another or vary depending on the time between doses, in order to account for the active lifetime of the present compounds in the body.